Date: 2015-12-05
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston
Company: Agios Pharmaceuticals (USA - MA)
Product: AG-120 - isocitrate dehydrogenase 1 (IDH1)-mutant inhibitor
Action
mechanism: protein inhibitor. AG-120 is a first-in-class, orally available, selective, potent inhibitor of the mutated IDH1 (Isocitrate dehydrogenase 1) protein, and is a highly targeted investigational medicine for the treatment of patients with cancers that harbor an IDH1 mutation. Isocitrate dehydrogenase (IDH) 1 and 2 are metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies, including acute myelogenous leukemia (AML) and glioma, a type of aggressive brain tumor with poor prognosis. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH creates a molecule that alters the cells’ genetic programming, and instead of maturing, the cells remain primitive and proliferate quickly. AG-120 is being developed in collaboration with Celgene.
Disease: advanced hematologic malignancies including elapsed or refractory acute myeloid leukemia (AML), untreated AML and other IDH1-mutated positive hematologic malignancies
Therapeutic area: Cancer - Oncology - Rare diseases
Country: France, USA
Trial
details: The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced hematologic malignancies that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where three cohorts of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs. (NCT02074839)
Latest
news: * On December 5, 2015, Agios Pharmaceuticals announced new data from the ongoing Phase 1 study evaluating single agent AG-120, a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-1 (IDH1), in advanced hematologic malignancies. The data are being presented at the 2015 American Society of Hematology Annual Meeting and Exposition (ASH) taking place December 5-8, 2015 in Orlando . AG-120 is being developed in collaboration with Celgene . Data as of October 1, 2015 from 87 patients with advanced IDH1 mutant positive hematologic malignancies confirmed a favorable safety profile consistent with previously reported data and showed durable clinical activity in 78 dose-escalation patients. Twenty-nine patients remain on study as of the analysis. Efficacy data is provided from the dose-escalation phase of the study only, where an overall response rate of 35 percent (27 of 78 response-evaluable patients) and a complete remission rate of 15 percent (12 of 78 response-evaluable patients) were observed. Patients were on study treatment for up to 14.1 months with a median duration of treatment of 2.9 months (ranging from 0.1 to 14.1 months). Data continue to show durable clinical activity for AG-120, with responses maintained for up to 12.5 months and a median duration of response of 5.6 months (previously unreported). * On November 8, 2015, Agios Pharmaceuticals announced the first data from the dose-escalation portion of the ongoing Phase 1 study evaluating single agent AG-120 in advanced solid tumors. The data are being presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston. The ongoing Phase 1 trial is assessing the safety and tolerability of AG-120 in advanced solid tumors, including glioma, intrahepatic cholangiocarcinoma (IHCC) and chondrosarcomas that harbor an IDH1 mutation in a dose-escalation phase followed by an expansion phase. As of September 3, 2015 (data cut-off), 62 patients have been treated with single agent AG-120, and 25 patients remain on treatment. Data reported at the meeting are from patients who received AG-120 administered from 200 mg to 1200 mg total daily doses in the dose-escalation arm. The median age of these patients is 56 (ranging from 23-88). Over half of the patients enrolled had high-grade tumors and received a median of three prior lines of therapy (ranging from one to six). Safety Data * On June 12, 2015, Agios Pharmaceuticals announced new data from the ongoing Phase 1 study evaluating single agent AG-120 in advanced hematologic malignancies presented at the 20th Congress of the European Hematology Association (EHA) taking place June 11-14, 2015 in Vienna . Data as of May 1, 2015 from 57 patients with advanced hematologic malignancies showed durable clinical activity and a favorable safety profile, with 25 patients on study as of the analysis. The study had an overall response rate of 31 percent (16 of 52 response-evaluable patients) and a complete remission rate of 15 percent (8 of 52 response-evaluable patients). Data continue to show durable clinical activity for AG-120, with responding patients on treatment for up to 11 months, and an estimated 79 percent of responders on treatment at three months. The overall safety profile remains consistent with 40 additional patients treated as of the last analysis. AG-120 is being evaluated in an ongoing Phase 1 trial in patients with AML and other IDH1-mutant positive advanced hematologic malignancies. Data reported are from patients receiving AG-120 administered from 100 mg to 1,200 mg total daily doses as of May 1, 2015 . The median age of these patients is 68 (ranging from 38-89). Treatment with AG-120 showed substantial reduction in the plasma levels of the oncometabolite 2-hydroxglutarate (2HG) to the level observed in healthy volunteers. This new data reflects responses in the evaluable population, which includes all patients with a pre-AG-120 screening assessment and day 28 or later response assessment or an earlier discontinuation for any reason. Patients with a screening assessment who were still on treatment, but had not reached the day 28 disease assessment, were excluded. A safety analysis was conducted for all 57 treated patients as of May 1, 2015 . The majority of adverse events reported by investigators were mild to moderate, with the most common being fatigue, diarrhea, pyrexia and nausea. 35 serious adverse events (SAEs) were reported, the majority being disease related, with four cases of leukocytosis potentially related to AG-120.
Agios looks forward to continuing to enroll our 125-patient expansion arm in relapsed/refractory AML and initiating two frontline studies to reach additional IDH1 mutant AML patients in need of better options.
AG-120 is being evaluated in an ongoing Phase 1 trial that includes a dose escalation phase and four expansion cohorts, including:
Arm 1: 125 IDH1 mutant positive AML patients who relapsed after bone marrow transplantation, are in second or later relapse, refractory to second line induction or reinduction treatment
Arm 2: 25 untreated IDH1 mutant positive AML patients who are not candidates for standard-of-care chemotherapy
Arm 3: 25 patients with other non-AML IDH1 mutant, relapsed or refractory advanced hematologic malignancies
Arm 4: 25 patients with relapsed IDH1 mutant positive AML not eligible for arm 1 or standard of care
Data reported are from patients treated with AG-120 administered from 100 mg to 1,200 mg total daily doses as of October 1, 2015 . The median age of these patients is 68 (ranging from 36-89). Patients received a median of two prior lines of therapy (ranging from zero to five). A safety analysis was conducted for all 87 treated patients and an efficacy analysis was conducted in the evaluable population of 78 dose-escalation patients, which includes all patients with a pre-AG-120 screening assessment and day 28 or later response assessment or an earlier discontinuation for any reason.
Safety Data: Of the 87 treated patients, 78 were from the dose-escalation phase and nine from the expansion.
The majority of adverse events reported by investigators were mild to moderate, with the most common being fatigue, diarrhea, pyrexia and nausea.
51 patients experienced at least one serious adverse event (SAE), the majority being disease related.
A maximum tolerated dose (MTD) has not been reached.
19 patients discontinued from the study due to death, and all were considered unrelated to AG-120.
All cause mortality at 30 and 60 days was 10.3 percent and 18.4 percent, respectively.
Efficacy Data
Twenty-seven out of 78 response-evaluable patients from the dose-escalation achieved investigator-assessed objective responses for an overall response rate of 35 percent.
Of the 27 patients who achieved an objective response, there were 12 complete remissions (CR), seven CRs with incomplete platelet recovery (CRp), six marrow CRs (mCR), one CR with incomplete hematologic recovery (CRi) and one partial remission (PR).
Patients were on study treatment for up to 14.1 months with a median duration of treatment of 2.9 months (ranging from 0.1 to 14.1 months).
Data continue to show durable clinical activity for AG-120, with responses maintained for up to 12.5 months and a median duration of response of 5.6 months.
The safety analysis conducted for all 62 treated patients as of September 3, 2015 demonstrated that AG-120 was well-tolerated with a favorable safety profile in advanced solid tumors including glioma, IHCC and chondrosarcoma. Specifically the analysis showed:
No dose limiting toxicities have been observed.
The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, diarrhea, vomiting, anemia and QT prolongation.
The majority of serious adverse events (SAE) were disease-related.
A maximum tolerated dose (MTD) has not been reached.
Efficacy Data: Agios also analyzed efficacy data from 55 response-evaluable patients as of September 3, 2015 , which showed:
Treatment with AG-120 showed substantial reduction of the oncometabolite 2-hydroxglutarate (2HG) in plasma and tumor tissue.
Imaging (magnetic resonance spectroscopy) results suggest that AG-120 can lower 2HG in the brain.
Chondrosarcoma: Seven of the 11 patients with IDH1 mutant positive chondrosarcoma had stable disease. Five of these patients maintained stable disease for six months or more. The six-month clinical benefit response rate was 5/9 or 56 percent.
IHCC: One out of 20 patients with IDH1 mutant positive IHCC had a partial response (PR) and 11 patients had stable disease. Six of these patients, including one with a PR and five with stable disease, maintained their response for six months or more. The six-month clinical benefit response rate was 6/14 or 43 percent.
Glioma: Ten out of 20 patients with IDH1 mutant positive glioma had stable disease. Four of these patients maintained stable disease for six months or more. The six-month clinical benefit response rate was 4/16 or 25 percent.
Other: One of the four patients with other IDH1 mutant positive solid tumors had stable disease.
Next Steps for AG-120 in Solid Tumors
Currently enrolling four expansion cohorts of 25 patients each, who receive the recommended dose of 500 mg of AG-120 once daily, with:
Low grade glioma with = six months of prior scans to assess volumetric changes
Second-line cholangiocarcinoma
High grade (metastatic) chondrosarcoma
Other solid tumors with an IDH1 mutation
Agios intends to initiate a randomized Phase 2 study of AG-120 in cholangiocarcinoma in 2016.
A maximum tolerated dose (MTD) has not been reached. 13 deaths were reported, and all were considered unrelated to AG-120.
Efficacy Data: Sixteen out of 52 response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 31 percent as of May 1, 2015 .
Of the 16 patients who achieved an objective response, there were eight complete remissions (CR), one complete remission with incomplete platelet recovery (CRp), three marrow complete remissions (mCR) and four partial remissions (PR).
Responses were durable, with duration on study drug as long as 11 months and ongoing. As of the analysis date, an estimated 79 percent of responders were on treatment for three months or longer, and 50 percent of responders were on treatment for six months or longer. "The durable clinical activity observed with AG-120 in such a refractory patient population is impressive," said Stéphane de Botton, M.D., the principal investigator at the Institut de Cancérologie Gustave Roussy , Villejuif, France . "These findings provide additional evidence that AG-120 can inhibit the IDH1-mutant protein allowing for cancer cells to appropriately mature. AG-120 has the potential to improve outcomes in patients with IDH1 mutant cancers." "These encouraging data represent the tremendous progress to date in our AG-120 program, as this therapy is proving to be well tolerated and effective, with an objective response rate of 31 percent of treated patients and duration on study up to 11 months," said Chris Bowden , M.D., chief medical officer of Agios. "Along with the insight gained from the AG-221 program, we are excited to move the AG-120 program forward rapidly with our partner Celgene . Our goal is to reach patients in need quickly, as evidenced by the recent announcement of our plans to initiate three expansion cohorts as part of the Phase 1 study."
